• Maximum tolerated dose [ Designated as safety issue: Yes ]
  
• Optimal biologic dose [ Designated as safety issue: No ]
  
• Toxicity [ Designated as safety issue: Yes ]
  

• Immunogenicity [ Designated as safety issue: No ]
  
• Pharmacokinetics [ Designated as safety issue: No ]
  
• Clinical response [ Designated as safety issue: No ]
  

OBJECTIVES:

Primary

• To determine the maximum tolerated dose (MTD) of DI-Leu16-IL2 after peripheral blood B-cell depletion with rituximab in patients with B-cell non-Hodgkin lymphoma (NHL).
• To investigate the optimal biologic dose (OBD) in patients treated with this regimen.
• To describe the toxicities associated with this regimen.

Secondary

• To evaluate the immunogenicity as measured by the induction of DI-Leu16-IL2-specific antibodies.
• To evaluate the pharmacokinetics of this regimen.
• To document any clinical responses associated with this regimen and survival endpoints of the these patients.

OUTLINE: This is a dose-escalation study of de-immunized DI-Leu16-IL2 immunocytokine.

Patients with detectable B-cells undergo peripheral blood B-cell depletion comprising rituximab IV on days 1 and 22 and receive de-immunized DI-Leu16-IL2 immunocytokine IV over 4 hours on days 2 and 4 (week 1) and 23 and 25 (week 4). Treatment repeats every 6 weeks for 2 courses. Patients with no detectable B-cells but a rituximab level < 10 μg/mL receive a single dose of rituximab to bring the level above 10 μg/mL and B-cell count is rechecked on days 1 and 23 prior to infusion of DI-Leu16-IL2. If B-cell levels are still detectable, the DI-Leu16-IL2 infusion is delayed one day and the levels are tested again on day 3. If B-cells have cleared, the DI-Leu16-IL2 infusion is given on days 3 and 5. If B-cells have not cleared by this time point, the patient is taken off study. The B-cell count and rituximab level are checked again on day 18 and additional rituximab is administered on day 22 according to the same criteria. This process is repeated for each course given.

Patients undergo blood sample collection periodically for pharmacokinetic studies. Samples are also analyzed for DI-Leu16-IL2 specific antibodies; changes in absolute number of NK cells, T-regulatory (Treg) cells, CD8 and CD4 T-cells and their activation status via flow cytometry; the relationship of changes in surface expression of IL-2 receptors (i.e., CD25 and CD122) to lymphocytosis, possible receptor-mediated clearance from the circulation, activation-induced apoptosis, and potential clinical adverse events; the effects of treatment on the Treg compartment (in the periphery and lymph node microenvironment) and to compare the effect on Treg cells with effects on total T-cell CD4, CD8, and NK cell numbers; to quantify levels of total T-cell, CD4 T-cells, CD8 T-cells, and CD56 (NK cells) as well as specific primer pairs via quantitative reverse-transcriptase PCR ; to evaluate NK cytotoxic activity via flow cytometric analysis; T-cell activity in response to common recall antigen via CFSE-based proliferation assay; cytokine levels, IL-6 and IL-10 levels, and tumor necrosis factor alpha levels via ELISA and correlate them with clinical and biological parameters; for soluble interleukin-2 receptor; and to assess the correlation of neopterin levels with the safety/side-effect profile.

Patients also undergo biopsy and blood sample collection periodically to correlate systemic immune responses represented by peripheral blood samples with local inflammatory changes analyzed from lymph node biopsy specimens; and to evaluate T-cell and NK cell infiltration in pre- and post-treatment biopsy samples via immunohistochemistry, ELISPOT assay, and/or flow cytometry.

After completion of study therapy, patients are followed periodically for 5 years.